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This study examines the sex-specific effects of gestational exposure (days 6-21) to endocrine-disrupting chemicals such as bisphenol A (BPA), diethylhexyl phthalate (DEHP), or their combination on brain monoamine levels that play an important role in regulating behavior. Pregnant Sprague-Dawley rats were orally administered saline, low doses (5 µg/kg BW/day) of BPA or DEHP, and their combination or a high dose (7.5 mg/kg BW/day) of DEHP alone or in combination with BPA during pregnancy. The offspring were subjected to a behavioral test and sacrificed in adulthood, and the brains were analyzed for neurotransmitter levels. In the paraventricular nucleus, there was a marked reduction in dopamine levels (p < 0.01) in male offspring from the BPA, DEHP, and B + D (HD) groups, which correlated well with their shock probe defensive burying times. Neurotransmitter changes in all brain regions examined were significant in female offspring, with DEHP (HD) females being affected the most, followed by the B + D groups. BPA and/or DEHP (LD) increased monoamine turnover in a region-specific manner in male offspring (p < 0.05). Overall, prenatal exposure to BPA, DEHP, or their combination alters monoamine levels in a brain region-specific, sex-specific, and dose-dependent manner, which could have implications for their behavioral and neuroendocrine effects.
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Background: Prenatal exposures to endocrine disrupting chemicals (EDCs) are correlated with adverse behavioral outcomes, but the effects of combinations of these chemicals are unclear. The aim of this study was to determine the dose-dependent effects of prenatal exposure to EDCs on male and female behavior. Methods: Pregnant Sprague-Dawley rats were orally dosed with vehicle, bisphenol A (BPA) (5 µg/kg body weight (BW)/day), low-dose (LD) diethylhexyl phthalate (DEHP) (5 µg/kg BW/day), high-dose (HD) DEHP (7.5 mg/kg BW/day), a combination of BPA and LD-DEHP (B + D (LD)), or a combination of BPA and HD-DEHP (B + D (HD)) on gestational days 6-21. Adult offspring were subjected to the Open Field Test (OFT), Elevated Plus Maze (EPM), and Shock Probe Defensive Burying test (SPDB) in adulthood. Body, adrenal gland, and pituitary gland weights were collected at sacrifice. Corticosterone (CORT) was measured in the serum. Results: Female EDC-exposed offspring showed anxiolytic effects in the OFT, while male offspring were unaffected. DEHP (HD) male offspring demonstrated a feminization of behavior in the EPM. Most EDC-exposed male offspring buried less in the SPDB, while their female counterparts showed reduced shock reactivity, indicating sex-specific maladaptive alterations in defensive behaviors. Additionally, DEHP (LD) males and females and B + D (LD) females displayed increased immobility in this test. DEHP (LD) alone and in combination with BPA led to lower adrenal gland weights, but only in male offspring. Finally, females treated with a mixture of B + D (HD) had elevated CORT levels. Conclusion: Prenatal exposure to BPA, DEHP, or a mixture of the two, affects behavior, CORT levels, and adrenal gland weights in a sex- and dose-dependent manner.
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OBJECTIVE: Our goal is to investigate if microbiota composition modulates reward signaling and assess the role of the vagus in mediating microbiota to brain communication. METHODS: Male germ-free Fisher rats were colonized with gastrointestinal contents from chow (low fat (LF) ConvLF) or HF (ConvHF) fed rats. RESULTS: Following colonization, ConvHF rats consumed significantly more food than ConvLF animals. ConvHF rats displayed lower feeding-induced extracellular DOPAC levels (a metabolite of dopamine) in the Nucleus Accumbens (NAc) as well as reduced motivation for HF foods compared to ConvLF rats. Dopamine receptor 2 (DDR2) expression levels in the NAc were also significantly lower in ConvHF animals. Similar deficits were observed in conventionally raised HF fed rats, showing that diet-driven alteration in reward can be initiated via microbiota. Selective gut to brain deafferentation restored DOPAC levels, DRD2 expression, and motivational drive in ConvHF rats. CONCLUSIONS: We concluded from these data that a HF-type microbiota is sufficient to alter appetitive feeding behavior and that bacteria to reward communication is mediated by the vagus nerve.
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Eje Cerebro-Intestino , Conducta Alimentaria , Ratas , Masculino , Animales , Ácido 3,4-Dihidroxifenilacético , Conducta Alimentaria/fisiología , Recompensa , BacteriasRESUMEN
Severe traumatic brain injury (sTBI) survivors experience permanent functional disabilities due to significant volume loss and the brain's poor capacity to regenerate. Chondroitin sulfate glycosaminoglycans (CS-GAGs) are key regulators of growth factor signaling and neural stem cell homeostasis in the brain. However, the efficacy of engineered CS (eCS) matrices in mediating structural and functional recovery chronically after sTBI has not been investigated. We report that neurotrophic factor functionalized acellular eCS matrices implanted into the rat M1 region acutely after sTBI significantly enhanced cellular repair and gross motor function recovery when compared to controls 20 weeks after sTBI. Animals subjected to M2 region injuries followed by eCS matrix implantations demonstrated the significant recovery of "reach-to-grasp" function. This was attributed to enhanced volumetric vascularization, activity-regulated cytoskeleton (Arc) protein expression, and perilesional sensorimotor connectivity. These findings indicate that eCS matrices implanted acutely after sTBI can support complex cellular, vascular, and neuronal circuit repair chronically after sTBI.
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Lesiones Traumáticas del Encéfalo , Células-Madre Neurales , Animales , Encéfalo , Lesiones Traumáticas del Encéfalo/terapia , Ratas , RegeneraciónRESUMEN
The neuropeptide galanin has been implicated in stress-related neuropsychiatric disorders in humans and rodent models. While pharmacological treatments for these disorders are ineffective for many individuals, physical activity is beneficial for stress-related symptoms. Galanin is highly expressed in the noradrenergic system, particularly the locus coeruleus (LC), which is dysregulated in stress-related disorders and activated by exercise. Galanin expression is elevated in the LC by chronic exercise, and blockade of galanin transmission attenuates exercise-induced stress resilience. However, most research on this topic has been done in rats, so it is unclear whether the relationship between exercise and galanin is species specific. Moreover, use of intracerebroventricular (ICV) galanin receptor antagonists in prior studies precluded defining a causal role for LC-derived galanin specifically. Therefore, the goals of this study were twofold. First, we investigated whether physical activity (chronic wheel running) increases stress resilience and galanin expression in the LC of male and female mice. Next, we used transgenic mice that overexpress galanin in noradrenergic neurons (Gal OX) to determine how chronically elevated noradrenergic-derived galanin, alone, alters anxiogenic-like responses to stress. We found that three weeks of ad libitum access to a running wheel in their home cage increased galanin mRNA in the LC of mice, which was correlated with and conferred resilience to stress. The effects of exercise were phenocopied by galanin overexpression in noradrenergic neurons, and Gal OX mice were resistant to the anxiogenic effect of optogenetic LC activation. These findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress.SIGNIFICANCE STATEMENT Understanding the neurobiological mechanisms underlying behavioral responses to stress is necessary to improve treatments for stress-related neuropsychiatric disorders. Increased physical activity is associated with stress resilience in humans, but the neurobiological mechanisms underlying this effect are not clear. Here, we investigate a potential causal mechanism of this effect driven by the neuropeptide galanin from the main noradrenergic nucleus, the locus coeruleus (LC). We show that chronic voluntary wheel running in mice increases stress resilience and increases galanin expression in the LC. Furthermore, we show that genetic overexpression of galanin in noradrenergic neurons causes resilience to a stressor and the anxiogenic effects of optogenetic LC activation. These findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress.
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Neuronas Adrenérgicas/metabolismo , Galanina/metabolismo , Estrés Psicológico/metabolismo , Neuronas Adrenérgicas/fisiología , Animales , Femenino , Galanina/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Estrés Psicológico/genética , Estrés Psicológico/fisiopatologíaRESUMEN
The lack of effective therapies for moderate-to-severe traumatic brain injuries (TBIs) leaves patients with lifelong disabilities. Neural stem cells (NSCs) have demonstrated great promise for neural repair and regeneration. However, direct evidence to support their use as a cell replacement therapy for neural injuries is currently lacking. We hypothesized that NSC-derived extracellular vesicles (NSC EVs) mediate repair indirectly after TBI by enhancing neuroprotection and therapeutic efficacy of endogenous NSCs. We evaluated the short-term effects of acute intravenous injections of NSC EVs immediately following a rat TBI. Male NSC EV-treated rats demonstrated significantly reduced lesion sizes, enhanced presence of endogenous NSCs, and attenuated motor function impairments 4 weeks post-TBI, when compared with vehicle- and TBI-only male controls. Although statistically not significant, we observed a therapeutic effect of NSC EVs on brain lesion volume, nestin expression, and behavioral recovery in female subjects. Our study demonstrates the neuroprotective and functional benefits of NSC EVs for treating TBI and points to gender-dependent effects on treatment outcomes, which requires further investigation.
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Lesiones Traumáticas del Encéfalo/terapia , Vesículas Extracelulares/fisiología , Vesículas Extracelulares/trasplante , Neuroprotección/fisiología , Recuperación de la Función/fisiología , Trasplante de Células Madre/métodos , Animales , Lesiones Traumáticas del Encéfalo/fisiopatología , Movimiento Celular/fisiología , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Células-Madre Neurales/fisiología , Células-Madre Neurales/trasplante , Ratas , Ratas Sprague-DawleyRESUMEN
The neuropeptide galanin is a potential therapeutic target for treating stress-related disorders, such as post-traumatic stress disorder (PTSD); however, its effects on contextual fear conditioning (CFC), an accepted animal model of PTSD, are not well understood. Dysregulation of the medial prefrontal cortex (mPFC) is implicated in PTSD. We investigated the effects of galanin (1 ug) administrated bilaterally into the prelimbic cortex, a division of the mPFC, on the consolidation, expression, and extinction of CFC of male Sprague-Dawley rats. Galanin administration significantly reduced consolidation and expression of CFC, but had no effect on retention or retrieval of extinction learning. These data further implicate galanin as a potential therapeutic target for treating stress-related disorders, particularly those characterized by aberrant emotional memory.
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Galanina/farmacología , Consolidación de la Memoria/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Animales , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Extinción Psicológica/efectos de los fármacos , Miedo/fisiología , Galanina/metabolismo , Masculino , Memoria/fisiología , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Trastornos por Estrés Postraumático/tratamiento farmacológicoRESUMEN
PURPOSE: Oxidative and inflammatory processes play a major role in stress-induced neural atrophy. There is a wide body of literature linking oxidative and inflammatory stress with reductions in neurotrophic factors, stress resilience, and cognitive function. Based on their antioxidant and anti-inflammatory capacity, we investigated the effect of the dietary carotenoids lutein and zeaxanthin, along with the zeaxanthin isomer meso-zeaxanthin (collectively the "macular xanthophylls" [MXans]) on systemic brain-derived neurotrophic factor (BDNF) and anti-oxidant capacity (AOC), and the pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß. To investigate higher-order effects, we assessed cognitive performance. METHODS: 59 young (18-25â¯yrs.), healthy subjects participated in a 6-month, double-blind, placebo-controlled trial to evaluate the effects of MXan supplementation on the aforementioned serum parameters and cognitive performance. Subjects were randomly assigned to one of three groups: placebo, 13â¯mg, or 27â¯mg/day total MXans; all measures were taken at baseline and 6â¯months. Blood was obtained via fasting blood draw, and MXan concentration in the retina (termed macular pigment optical density [MPOD]) was measured via customized heterochromatic flicker photometry. Serum BDNF and cytokines were assessed via ELISA. Serum antioxidant capacity (AOC) and serum MXan concentrations were quantified via colorimetric microplate assay, and high-performance liquid chromatography, respectively. Cognitive performance was measured via a computer-based assessment tool (CNS Vital Signs). RESULTS: BDNF, MPOD, serum MXans, and AOC all increased significantly versus placebo in both treatment groups over the 6-month study period (pâ¯<â¯.05 for all). IL-1ß decreased significantly versus placebo in both treatment groups (pâ¯=â¯.0036 and pâ¯=â¯.006, respectively). For cognitive measures, scores for composite memory, verbal memory, sustained attention, psychomotor speed, and processing speed all improved significantly in treatment groups (pâ¯<â¯.05 for all) and remained unchanged in the placebo group. Several measures were found to be significantly associated in terms of relational changes over the course of the study. Notably, change in BDNF was related to change in IL-1ß (râ¯=â¯-0.47; pâ¯<â¯.001) and MPOD (râ¯=â¯0.44; pâ¯=â¯.0086). Additionally, changes in serum MXans were strongly related to AOC (râ¯=â¯0.79 & 0.61 for lutein and zeaxanthin isomers respectively; pâ¯<â¯.001). For cognitive scores, change in BDNF was correlated to change in composite memory (râ¯=â¯0.32; pâ¯=â¯.014) and verbal memory (râ¯=â¯0.35; pâ¯=â¯.007), whereas change in MPOD was correlated with change in both psychomotor speed (râ¯=â¯0.38; pâ¯=â¯.003), and processing speed (râ¯=â¯0.35; pâ¯=â¯.007). Change in serum lutein was found to be significantly correlated to change in verbal memory (râ¯=â¯0.41; pâ¯<â¯.001), composite memory (râ¯=â¯0.31; pâ¯=â¯.009), and sustained attention (râ¯=â¯0.28; pâ¯=â¯.036). Change in serum zeaxanthin isomers was significantly correlated with change in verbal memory (râ¯=â¯0.33; pâ¯=â¯.017). Lastly, change in AOC was significantly associated with verbal memory (râ¯=â¯0.34; pâ¯=â¯.021), composite memory (râ¯=â¯0.29; pâ¯=â¯.03), and sustained attention (râ¯=â¯0.35; pâ¯=â¯.016). No significant relational changes in any cognitive parameter were found for the placebo group. CONCLUSIONS: Six months of daily supplementation with at least 13â¯mg of MXans significantly reduces serum IL-1ß, significantly increases serum MXans, BDNF, MPOD, and AOC, and improves several parameters of cognitive performance. Findings suggest that increased systemic antioxidant/anti-inflammatory capacity (and not necessarily deposition of the carotenoids in neural tissues), may explain many of the effects determined in this study. The significant relationship between change in BDNF and IL-1ß over the course of the study suggests that regular consumption of MXans interrupts the inflammatory cascade that can lead to reduction of BDNF. Changes in MPOD and BDNF appear to account for enhancement in cognitive parameters that involve speed of processing and complex processing, respectively. ISRCTN Clinical Trial Registration: ISRCTN16156382.
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Factor Neurotrófico Derivado del Encéfalo/sangre , Cognición/efectos de los fármacos , Interleucina-1beta/sangre , Interleucina-6/sangre , Luteína/farmacología , Factor de Necrosis Tumoral alfa/sangre , Zeaxantinas/farmacología , Adolescente , Adulto , Suplementos Dietéticos , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Masculino , Pruebas Neuropsicológicas , Adulto JovenRESUMEN
PURPOSE: Oxidative stress and systemic inflammation are the root cause of several deleterious effects of chronic psychological stress. We hypothesize that the antioxidant and anti-inflammatory capabilities of the macular carotenoids (MCs) lutein, zeaxanthin, and meso-zeaxanthin could, via daily supplementation, provide a dietary means of benefit. METHODS: A total of 59 young healthy subjects participated in a 12-month, double-blind, placebo-controlled trial to evaluate the effects of MC supplementation on blood cortisol, psychological stress ratings, behavioural measures of mood, and symptoms of sub-optimal health. Subjects were randomly assigned to one of three groups: placebo, 13â mg, or 27â mg / day total MCs. All parameters were assessed at baseline, 6 months, and 12 months. Serum MCs were determined via HPLC, serum cortisol via ELISA, and macular pigment optical density (MPOD) via customized heterochromatic flicker photometry. Behavioural data were obtained via questionnaire. RESULTS: Significant baseline correlations were found between MPOD and Beck anxiety scores (râ =â -0.28; Pâ =â 0.032), MPOD and Brief Symptom Inventory scores (râ =â 0.27; Pâ =â 0.037), and serum cortisol and psychological stress scores (râ =â 0.46; Pâ <â 0.001). Supplementation for 6 months improved psychological stress, serum cortisol, and measures of emotional and physical health (Pâ <â 0.05 for all), versus placebo. These outcomes were either maintained or improved further at 12 months. CONCLUSIONS: Supplementation with the MCs significantly reduces stress, cortisol, and symptoms of sub-optimal emotional and physical health. Determining the basis for these effects, whether systemic or a more central (i.e. brain) is a question that warrants further study.
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Antioxidantes/administración & dosificación , Carotenoides/administración & dosificación , Hidrocortisona/sangre , Estrés Psicológico/dietoterapia , Adolescente , Adulto , Síntomas Conductuales/psicología , Suplementos Dietéticos , Método Doble Ciego , Femenino , Humanos , Luteína/administración & dosificación , Luteína/sangre , Mácula Lútea , Pigmento Macular/farmacología , Masculino , Pigmentos Retinianos , Autoinforme , Adulto Joven , Zeaxantinas/administración & dosificación , Zeaxantinas/sangreRESUMEN
The neuropeptide galanin is widely distributed in the central and peripheral nervous systems and part of a bigger family of bioactive peptides. Galanin exerts its biological activity through three G-protein coupled receptor subtypes, GAL1-3R. Throughout the last 20years, data has accumulated that galanin can have a neuroprotective effect presumably mediated through the activation of GAL1R and GAL2R. In order to test the pharmaceutical potential of galanin receptor subtype selective ligands to inhibit excitotoxic cell death, the GAL1R selective ligand M617 and the GAL2R selective ligand M1145 were compared to the novel GAL1/2R ligand M1154, in their ability to reduce the excitotoxic effects of intracerebroventricular injected kainate acid in rats. The peptide ligands were evaluated in vitro for their binding preference in a competitive (125)I-galanin receptor subtype binding assay, and G-protein signaling was evaluated using both classical signaling and a label-free real-time technique. Even though there was no significant difference in the time course or severity of the kainic acid induced epileptic behavior in vivo, administration of either M617 or M1154 before kainic acid administration significantly attenuated the neuronal cell death in the hippocampus. Our results indicate the potential therapeutic value of agonists selective for GAL1R in the prevention of neuronal cell death.
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Bradiquinina/análogos & derivados , Galanina/análogos & derivados , Hipocampo/patología , Neuronas/metabolismo , Neuronas/patología , Fragmentos de Péptidos/farmacología , Receptor de Galanina Tipo 1/metabolismo , Receptor de Galanina Tipo 2/metabolismo , Animales , Bradiquinina/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , AMP Cíclico/metabolismo , Galanina/farmacología , Hipocampo/efectos de los fármacos , Humanos , Ácido Kaínico/toxicidad , Ligandos , Masculino , Neuronas/efectos de los fármacos , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptor de Galanina Tipo 1/agonistas , Receptor de Galanina Tipo 2/agonistasRESUMEN
Decades of research confirm that noradrenergic locus coeruleus (LC) neurons are essential for arousal, attention, motivation, and stress responses. While most studies on LC transmission focused unsurprisingly on norepinephrine (NE), adrenergic signaling cannot account for all the consequences of LC activation. Galanin coexists with NE in the vast majority of LC neurons, yet the precise function of this neuropeptide has proved to be surprisingly elusive given our solid understanding of the LC system. To elucidate the contribution of galanin to LC physiology, here we briefly summarize the nature of stimuli that drive LC activity from a neuroanatomical perspective. We go on to describe the LC pathways in which galanin most likely exerts its effects on behavior, with a focus on addiction, depression, epilepsy, stress, and Alzheimer׳s disease. We propose a model in which LC-derived galanin has two distinct functions: as a neuromodulator, primarily acting via the galanin 1 receptor (GAL1), and as a trophic factor, primarily acting via galanin receptor 2 (GAL2). Finally, we discuss how the recent advances in neuropeptide detection, optogenetics and chemical genetics, and galanin receptor pharmacology can be harnessed to identify the roles of LC-derived galanin definitively. This article is part of a Special Issue entitled SI: Noradrenergic System.
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Conducta/fisiología , Galanina/metabolismo , Locus Coeruleus/metabolismo , Animales , Humanos , Locus Coeruleus/anatomía & histología , Vías Nerviosas/anatomía & histología , Vías Nerviosas/metabolismo , Neuronas/citología , Neuronas/metabolismo , FenotipoRESUMEN
In the United States, more than ten million women use contraceptive hormones. Ethinyl estradiol and levonorgestrel have been mainstay contraceptive hormones for the last four decades. Surprisingly, there is scant information regarding their action on the central nervous system and behavior. Intact female rats received three weeks of subcutaneous ethinyl estradiol (10 or 30µg/rat/day), levonorgestrel (20 or 60µg/rat/day), a combination of both (10/20µg/rat/day and 30/60µg/rat/day), or vehicle. Subsequently, the rats were tested in three versions of the novel object recognition test to assess learning and memory, and a battery of tests for anxiety-like behavior. Serum estradiol and ovarian weights were measured. All treatment groups exhibited low endogenous 17ß-estradiol levels at the time of testing. Dose-dependent effects of drug treatment manifested in both cognitive and anxiety tests. All low dose drugs decreased anxiety-like behavior and impaired performance on novel object recognition. In contrast, the high dose ethinyl estradiol increased anxiety-like behavior and improved performance in cognitive testing. In the cell molecular analyses, low doses of all drugs induced a decrease in tyrosine hydroxylase mRNA and protein in the locus coeruleus. At the same time, low doses of ethinyl estradiol and ethinyl estradiol/levonorgestrel increased galanin protein in this structure. Consistent with the findings above, the low dose treatments of ethinyl estradiol and combination ethinyl estradiol/levonorgestrel reduced brain-derived neurotrophic factor mRNA in the hippocampus. These effects of ethinyl estradiol 10µg alone and in combination with levonorgestrel 20µg suggest a diminution of norepinephrine input into the hippocampus resulting in a decline in learning and memory.
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Ansiedad/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cognición/efectos de los fármacos , Etinilestradiol/farmacología , Hipocampo/efectos de los fármacos , Levonorgestrel/farmacología , Locus Coeruleus/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/genética , Femenino , Hipocampo/metabolismo , Aprendizaje/efectos de los fármacos , Locus Coeruleus/metabolismo , Memoria/efectos de los fármacos , Ratas , Tirosina 3-Monooxigenasa/genéticaRESUMEN
Our laboratory has previously reported that chronic, voluntary exercise diminishes seizure-related behaviors induced by convulsant doses of kainic acid. The present experiments tested the hypothesis that exercise exerts this protective effect through a mechanism involving suppression of glutamate release in the hippocampal formation. Following three weeks of voluntary wheel running or sedentary conditions, rats were injected with 10 mg/kg of kainic acid, and hippocampal glutamate was measured in real time using a telemetric, in vivo voltammetry system. A separate experiment measured electroencephalographic (EEG) activity following kainic acid treatment. Results of the voltammetry experiment revealed that the rise in hippocampal glutamate induced by kainic acid is attenuated in exercising rats compared to sedentary controls, indicating that the exercise-induced protection against seizures involves regulation of hippocampal glutamate release. The findings reveal the potential benefit of regular exercise in the treatment and prevention of seizure disorders and suggest a possible neurobiological mechanism underlying this effect.
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Ácido Glutámico/metabolismo , Hipocampo/fisiopatología , Carrera/fisiología , Convulsiones/fisiopatología , Animales , Modelos Animales de Enfermedad , Electroencefalografía , Vivienda para Animales , Ácido Kaínico , Masculino , Distribución Aleatoria , Ratas Sprague-Dawley , TelemetríaRESUMEN
Relapse represents one of the most significant problems in the long-term treatment of drug addiction. Cocaine blocks plasma membrane monoamine transporters and increases dopamine (DA) overflow in the brain, and DA is critical for the motivational and primary reinforcing effects of the drug as well as cocaine-primed reinstatement of cocaine seeking in rats, a model of relapse. Thus, modulators of the DA system may be effective for the treatment of cocaine dependence. The endogenous neuropeptide galanin inhibits DA transmission, and both galanin and the synthetic galanin receptor agonist, galnon, interfere with some rewarding properties of cocaine. The purpose of this study was to further assess the effects of galnon on cocaine-induced behaviors and neurochemistry in rats. We found that galnon attenuated cocaine-induced motor activity, reinstatement and DA overflow in the frontal cortex at a dose that did not reduce baseline motor activity, stable self-administration of cocaine, baseline extracellular DA levels or cocaine-induced DA overflow in the nucleus accumbens (NAc). Similar to cocaine, galnon had no effect on stable food self-administration but reduced food-primed reinstatement. These results indicate that galnon can diminish cocaine-induced hyperactivity and relapse-like behavior, possibly in part by modulating DA transmission in the frontal cortex.
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Cocaína/farmacología , Cumarinas/farmacología , Inhibidores de Captación de Dopamina/farmacología , Lóbulo Frontal/metabolismo , Animales , Trastornos Relacionados con Cocaína/fisiopatología , Trastornos Relacionados con Cocaína/prevención & control , Condicionamiento Operante , Dopamina/metabolismo , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Galanina/antagonistas & inhibidores , Masculino , Microdiálisis , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/metabolismo , Ratas Sprague-Dawley , Recurrencia , Refuerzo en Psicología , AutoadministraciónRESUMEN
RATIONALE: Voluntary aerobic exercise has shown promise as a treatment for substance abuse, reducing relapse in cocaine-dependent people. Wheel running also attenuates drug-primed and cue-induced reinstatement of cocaine seeking in rats, an animal model of relapse. However, in most of these studies, wheel access was provided throughout cocaine self-administration and/or extinction and had effects on several parameters of drug seeking. Moreover, the effects of exercise on footshock stress-induced reinstatement have not been investigated. OBJECTIVES: The purposes of this study were to isolate and specifically examine the protective effect of exercise on relapse-like behavior elicited by a drug prime or stress. METHODS: Rats were trained to self-administer cocaine at a stable level, followed by extinction training. Once extinction criteria were met, rats were split into exercise (24 h, continuous access to running wheel) and sedentary groups for 3 weeks, after which, drug-seeking behavior was assessed following a cocaine prime or footshock. We also measured galanin messenger RNA (mRNA) in the locus coeruleus and A2 noradrenergic nucleus. RESULTS: Exercising rats ran â¼4-6 km/day, comparable to levels previously reported for rats without a history of cocaine self-administration. Post-extinction exercise significantly attenuated cocaine-primed, but not footshock stress-induced, reinstatement of cocaine seeking, and increased galanin mRNA expression in the LC but not A2. CONCLUSION: These results indicate that chronic wheel running can attenuate some forms of reinstatement, even when initiated after the cessation of cocaine self-administration, supporting the idea that voluntary exercise programs may help maintain abstinence in clinical populations.
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Conducta Adictiva/prevención & control , Conducta Adictiva/psicología , Cocaína/administración & dosificación , Extinción Psicológica , Condicionamiento Físico Animal/psicología , Estrés Psicológico/psicología , Animales , Trastornos Relacionados con Cocaína/prevención & control , Trastornos Relacionados con Cocaína/psicología , Extinción Psicológica/fisiología , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Condicionamiento Físico Animal/fisiología , Ratas , Ratas Sprague-Dawley , Autoadministración , Estrés Psicológico/complicacionesRESUMEN
Current concepts of the neurobiology of stress-related disorders, such as anxiety and depression emphasize disruptions in neural plasticity and neurotrophins. The potent trophic actions of exercise, therefore, represent not only an effective means for prevention and treatment of these disorders, they also afford the opportunity to employ exercise paradigms as a basic research tool to uncover the neurobiological mechanisms underlying these disorders. Novel approaches to studying stress-related disorders focus increasingly on trophic factor signaling in corticolimbic circuits that both mediate and regulate cognitive, behavioral, and physiological responses to deleterious stress. Recent evidence demonstrates that the neural plasticity supported by these trophic mechanisms is vital for establishing and maintaining resilience to stress. Therapeutic interventions that promote these mechanisms, be they pharmacological, behavioral, or environmental, may therefore prevent or reverse stress-related mental illness by enhancing resilience. The present paper will provide an overview of trophic mechanisms responsible for the enhancement of resilience by voluntary exercise with an emphasis on brain-derived neurotrophic factor, galanin, and interactions between these two trophic factors.
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UNLABELLED: Rats selectively bred for high- and low-capacity for running on a treadmill (HCR; LCR) also differ in wheel-running behavior, but whether wheel-running can be explained by intrinsic or adaptive brain mechanisms is not as yet understood. It is established that motivation of locomotory behavior is driven by dopaminergic transmission in mesolimbic and mesostriatal systems. However, whether voluntary wheel running is associated with enkephalinergic activity in the ventral striatum is not known. MATERIALS AND METHODS: 40 male (20 HCR and 20 LCR) and 40 female (20 HCR and 20 LCR) rats were randomly assigned to 3 weeks of activity wheel exposure or sedentary conditions without wheel access. After 3 weeks of activity-wheel running, rats were decapitated and brains were extracted. Coronal sections were analyzed utilizing in situ hybridization histochemistry for enkephalin (ENK) mRNA in the ventral striatum. RESULTS: HCR rats expressed less ENK than LCR rats in the nucleus accumbens among females (p<0.01) and in the olfactory tubercle among both females (p<0.05) and males (p<0.05). There was no effect of wheel running on ENK mRNA expression. CONCLUSION: Line differences in ENK expression in the olfactory tubercle, and possibly the nucleus accumbens, partly explain divergent wheel-running behavior. The lower striatal ENK in the HCR line is consistent with enhanced dopaminergic tone, which may explain the increased motivation for wheel running observed in the HCR line.
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Encefalinas/metabolismo , Actividad Motora , Estriado Ventral/metabolismo , Animales , Encefalinas/genética , Femenino , Masculino , Núcleo Accumbens/metabolismo , Tubérculo Olfatorio/metabolismo , ARN Mensajero/metabolismo , Ratas , Carrera/fisiologíaRESUMEN
The bidirectional comorbidity between epilepsy and depression is associated with severe challenges for treatment efficacy and safety, often resulting in poor prognosis and outcome for the patient. We showed previously that rats selectively bred for depression-like behaviors (SwLo rats) also have increased limbic seizure susceptibility compared with their depression-resistant counterparts (SwHi rats). In this study, we examined the therapeutic efficacy of voluntary exercise in our animal model of epilepsy and depression comorbidity. We found that chronic wheel running significantly increased both struggling duration in the forced swim test and latency to pilocarpine-induced limbic motor seizure in SwLo rats but not in SwHi rats. The antidepressant and anticonvulsant effects of exercise were associated with an increase in galanin mRNA specifically in the locus coeruleus of SwLo rats. These results demonstrate the beneficial effects of exercise in a rodent model of epilepsy and depression comorbidity and suggest a potential role for galanin.
Asunto(s)
Depresión , Epilepsia/rehabilitación , Condicionamiento Físico Animal/fisiología , Natación/fisiología , Animales , Depresión/fisiopatología , Depresión/psicología , Depresión/rehabilitación , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/psicología , Epilepsia/inducido químicamente , Epilepsia/fisiopatología , Galanina/genética , Galanina/metabolismo , Regulación de la Expresión Génica/fisiología , Locomoción/fisiología , Locus Coeruleus/metabolismo , Masculino , Agonistas Muscarínicos/toxicidad , Pilocarpina/toxicidad , ARN Mensajero/metabolismo , Ratas , Estadísticas no ParamétricasRESUMEN
Although physical activity reduces anxiety in humans, the neural basis for this response is unclear. Rodent models are essential to understand the mechanisms that underlie the benefits of exercise. However, it is controversial whether exercise exerts anxiolytic-like potential in rodents. Evidence is reviewed to evaluate the effects of wheel running, an experimental mode of exercise in rodents, on behavior in tests of anxiety and on norepinephrine and galanin systems in neural circuits that regulate stress. Stress is proposed to account for mixed behavioral findings in this literature. Indeed, running promotes an adaptive response to stress and alters anxiety-like behaviors in a manner dependent on stress. Running amplifies galanin expression in noradrenergic locus coeruleus (LC) and suppresses stress-induced activity of the LC and norepinephrine output in LC-target regions. Thus, enhanced galanin-mediated suppression of brain norepinephrine in runners is supported by current literature as a mechanism that may contribute to the stress-protective effects of exercise. These data support the use of rodents to study the emotional and neurobiological consequences of exercise.
Asunto(s)
Ansiedad/psicología , Encéfalo/metabolismo , Galanina/metabolismo , Norepinefrina/metabolismo , Condicionamiento Físico Animal/psicología , Estrés Psicológico/psicología , Animales , Ansiedad/metabolismo , Condicionamiento Físico Animal/fisiología , Ratas , Estrés Psicológico/metabolismoRESUMEN
Although exercise improves anxiety in humans, it is controversial whether exercise is anxiolytic in rodents. We tested the hypothesis that stress influences the effect of exercise on anxiety-like and defensive behaviors. To explore the neurobiological mechanisms of exercise, we also examined whether exercise alters gene expression for the stress-related peptide galanin. Rats were housed in the presence or absence of a running wheel for 21 d. A subset of these rats were (1) not injected or received a single high, dose of the ß-carboline FG7142 (inverse agonist at the benzodiazepine receptor site) immediately prior to testing or (2) were injected repeatedly with vehicle or FG7142 during the last 10d of exercise. On day 22, anxiety-like and defensive behaviors were measured in the elevated plus maze, shock probe defensive burying, and defensive withdrawal tests. Locus coeruleus prepro-galanin mRNA was measured by in situ hybridization. Exercise and sedentary rats that were not injected exhibited similar behavior in all tests, whereas FG7142 injected immediately prior to the test battery produced intense avoidance and immobility consistent with an anxiety-like response. However, exercise produced anxiolytic-like and active defensive behaviors in the test battery relative to the sedentary condition in rats injected repeatedly with vehicle or FG7142. Exercise also increased prepro-galanin mRNA in the locus coeruleus relative to sedentary controls. These data suggest that the emergence of enhanced adaptive behavior after chronic voluntary exercise is influenced by stress. Our data support a role for galanin in the beneficial consequences of wheel running.